The primary objectives of the studies proposed in this application are to define the parameters which maintain self-tolerance to liver-specific F-antigen and to ascertain the mechanism(s) governing dominant nonresponsiveness to this antigen. A study is also planned of the role of the non H-2 linked regulatory gene (previously described) in the immune response to F-antigen. Long-term objectives are a determination of the function of F-antigen which is found in the livers of all mammals tested, as well as a determination of whether F-antigen is released in various forms of liver disease and the possible effects of such release on the course of the disease. These investigations will be performed primarily in the mouse and will employ the radioimmunoassay developed for F-antigen. An attempt will be made to circumvent the induction of self-tolerance to F-antigen in F1 hybrid radiation chimeras reconstituted with parental bone marrow cells treated in vitro with anti-theta serum. Cells from such mice will be transferred with appropriate normal cells to ascertain whether the mechanism governing self-tolerance induction is the same as that governing dominant nonresponsiveness.